Serum cholesterol lowering agent or preventive or therapeutic agent for atherosclerosis

ABSTRACT

A serum cholesterol lowing agent or a preventive or therapeutile agent for atherosclerosis, which each comprises a combination of a compound represented by the following general formula (I) or pharmaceutical acceptable salts thereof with a cholesterol biosynthesis inhibitor and/or a fibrate type cholesterol lowing agent. (I) (b) (a) [In the formula, A 1 , A 2 , A 3  and A 4  each is hydrogen, a group represented by the formula (b), or a group represented by the formula (a), provided that at least one of these is a group represented by the formula (a); A 2  is C 1-5  alkyl etc; and n. p, q and r each is an integer of 0, 1 or 2.

FIELD OF THE INVENTION

The present invention relates to medicinal compositions that are usefulas serum cholesterol lowering agent or preventive or therapeutic agentfor atherosclerosis, in more detail, relates to medicinal compositionsof β-lactam cholesterol absorption inhibitors containing C-glycoside inthose molecules combined with cholesterol biosynthesis inhibitors and/orfibrate-type cholesterol lowering agents.

BACKGROUND OF THE INVENTION

Conventionally, cholesterol biosynthesis inhibitors or fibrate-typecholesterol lowering agents have been widely used for serum cholesterolreduction and prevention or therapy of atherosclerosis, and proposingthe combination of β-lactam cholesterol absorption inhibitors andcholesterol biosynthesis inhibitors (JP 8-505141). The present applicanthas previously published that β-lactam cholesterol absorption inhibitorscontaining C-glycoside in those molecules have an excellent cholesterollowering action, and are useful as serum cholesterol lowering agents(WO-02/066464 A1).

The purpose of the present invention is supply of more excellent serumcholesterol lowering agent or preventive or therapeutic agent foratherosclerosis.

DISCLOSURE OF THE INVENTION

The present invention is serum cholesterol lowering agent or preventiveor therapeutic agent for atherosclerosis consist of the combination of acompound represented by the following general formula (I) orpharmaceutical acceptable salts and cholesterol biosynthesis inhibitorsand/or fibrate-type cholesterol lowering agents.

[wherein: A₁, A₃ and A₄ are hydrogen atom, halogen atom, alkyl grouphaving one to five carbon atoms, alkoxy group having one to five carbonatoms, —COOR₁, a following formula:

(wherein: R₁ is hydrogen atom or alkyl group having one to five carbonatoms) or a following formula:

[wherein: R₂ is —CH₂OH group, —CH₂OC(O)—R₁ group or —CO₂—R₁ group; R₃ is—OH group or —OC(O)—R₁ group; R₄ is —(CH₂)_(k)R₅(CH₂)₁— (k and l are 0or 1 more integer; k+1 is 10 or fewer integer) and binds totetrahydropyran ring by C—C bond. R₅ means single bond (—), —CH═CH—,—OCH₂—, carbonyl group or —CH(OH)—.] More than one of A₁, A₃ and A₄ informula (I) must be the group in above-mentioned formula (a). A₂ isalkyl chain having one to five carbon atoms, alkoxy chain having one tofive carbon atoms, alkenyl chain having one to five carbon atoms,hydroxyl alkyl chain having one to five carbon atoms or carbonyl alkylchain having one to five carbon atoms. n, p, q or r are 0, 1 or 2.]

Also, the present invention is serum cholesterol lowering agent orpreventive or therapeutic agent for atherosclerosis consist of themixture of a compound represented by the above general formula (I) orpharmaceutical acceptable salts and cholesterol biosynthesis inhibitorsand/or fibrate-type cholesterol lowering agents. Also, the presentinvention is serum cholesterol lowering agent or preventive ortherapeutic agent for atherosclerosis formed a kit by single packaging acontainer containing a compound represented by the above general formula(I) or pharmaceutical acceptable salts and a container containingcholesterol biosynthesis inhibitor and/or fibrate-type cholesterollowering agents. Also, it is able to administer a compound representedby the above general formula(I) or pharmaceutical acceptable salts andcholesterol biosynthesis inhibitors and/or fibrate-type cholesterollowering agents simultaneously or consecutively.

PREFERRED EMBODIMENT OF THE INVENTION

The present invention is serum cholesterol lowering agent or preventiveor therapeutic agent for atherosclerosis consisting of the combinationof a compound represented by the following general formula (I) orpharmaceutical acceptable salts and cholesterol biosynthesis inhibitorsand/or fibrate-type cholesterol lowering agents. Concretely, thiscombined medicine means: {circle around (1)} the medicine combined acompound represented by the general formula (I) or pharmaceuticalacceptable salts with cholesterol biosynthesis inhibitors, {circlearound (2)} the medicine combined a compound represented by the generalformula (I) or pharmaceutical acceptable salts with fibrate-typecholesterol lowering agents, {circle around (3)} the medicine combined acompound represented by the general formula (I) or pharmaceuticalacceptable salts with cholesterol biosynthesis inhibitors andfibrate-type cholesterol lowering agents. This combined usage meanscombined administration, and is able to administer simultaneously orconsecutively.

A compound represented by the above general formula (I) orpharmaceutical acceptable salts in the present invention have serumcholesterol lowering actions. These compounds are shown in WO-02/066464A1. These β-lactam compounds, which show cholesterol lowering actionsand has C-glycoside in those molecules, show synergistic effects byusing in combination with cholesterol biosynthesis inhibitors and/orfibrate-type cholesterol lowering agents for serum cholesterol loweringeffect or preventive or therapeutic effect for atherosclerosis.

A compound represented by the above general formula (I) orpharmaceutical acceptable salts using in the present invention are, forexample, the compounds shown in Table 1˜12. TABLE 1 No. Structure mp (°C.) [α]_(D) ²⁵/(C, Solv.) 1

89-90 −40.4 (C = 0.5, MeOH) 2

110-112 −33.2 (C = 0.5, MeOH) 3

56-58 4

76-78 5

73-75

TABLE 2 No. Structure mp (° C.) [α]_(D) ²⁵/(C, Solv.) 6

60-62 7

80-82 −46.7 (C = 0.3, MeOH) 8

56-58 9

84-86 −40.4 (C = 0.5, MeOH) 10

60-61

TABLE 3 No. Structure mp (° C.) [α]_(D) ²⁵/(C, Solv.) 11

74-75 12

65-67 (C = 0.5, CHCl₃) 13

64-66 14

61-62 15

64-65

TABLE 4 No. Structure mp (° C.) [α]_(D) ²⁵/(C, Solv.) 16

73-75 17

105-106 18

73-74 19

170-172 20

76-78

TABLE 5 No. Structure mp (° C.) [α]_(D) ²⁵/(C, Solv.) 21

161-162 22

115-117 −71.3 (C = 0.3, MeOH) 23

104-106 −110 (C = 0.5, MeOH) 24

102-104 −58.0 (C = 0.3, MeOH) 25

67-69 −62.8 (C = 0.5, MeOH)

TABLE 6 No. Structure mp (° C.) [α]_(D) ²⁵/(C, Solv.) 26

78-80 −67.2 (C = 0.5, MeOH) 27

104-106 −26.0 (C = 0.5, MeOH) 28

86-88 −35.7 (C = 0.6, MeOH) 29

148-150  −122.0 (C = 0.3, MeOH) 30

102-104 −52.0 (C = 0.3, MeOH)

TABLE 7 No. Structure mp (° C.) [α]_(D) ²⁵/(C, Solv.) 31

97-99 32

liq −39.3 (C = 0.8, MeOH) 33

82-84 −47.6 (C = 0.5, MeOH) 34

83-85 35

81-83

TABLE 8 No. Structure mp (° C.) [α]_(D) ²⁵/(C, Solv.) 36

79-81 37

80-82 38

200-201 −69.3 (C = 0.3, MeOH) 39

126-128 −42.66 (C = 0.3, MeOH) 40

78-80

TABLE 9 No. Structure mp (° C.) [α]_(D) ²⁵/(C, Solv.) 41

110-112 −67.2 (C = 0.5, MeOH) 42

56-58 −92.0 (C = 0.3, MeOH) 43

96-98 −40.4 (C = 0.5, CHCl₃) 44

84-86 −41.3 (C = 0.3, MeOH) 45

84-86 −64.0 (C = 0.25, MeOH)

TABLE 10 No. Structure mp (° C.) [α]_(D) ²⁵/(C, Solv.) 46

153-155  −54.66 (C = 0.25, MeOH) 47

72-74 −33.6 (C = 1.0, MeOH) 48

81-83 −21.8 (C = 1.0, MeOH) 49

111-113 −20.0 (C = 0.35, MeOH) 50

61-63 −48.6 (C = 0.14, MeOH)

TABLE 11 No. Structure mp (° C.) [α]_(D) ²⁵/(C, Solv.) 51

65-67 −42.8 (C = 0.25, MeOH) 52

79-81 −33.2 (C = 1.0, MeOH)  53

81-83 −29.4 (C = 0.5, MeOH)  54

69-71 −38.6 (C = 0.35, MeOH) 55

66-68 −42.9 (C = 0.35, MeOH)

TABLE 12 No. Structure mp (° C.) [α]_(D) ²⁵/(C, Solv.) 56

82-84 −49.2 (C = 1.0, MeOH) 57

116-118 −76.0 (C = 0.3, MeOH) 58

110-112 −40.3 (C = 0.7, MeOH)

Also, cholesterol biosynthesis inhibitors using in the present inventionis at least one sort chosen from the group consisit of HMG-CoA reductaseinhibitors, squalene synthase inhibitors and squalene epoxydaseinhibitors. HMG-CoA reductase inhibitors include, for example,pravastatin, lovastatin, fluvastatin, simvastatin, itavastatin,atorvastatin, cerivastatin, rosuvastatin, pitavastatin and carvastatin(TF802); squalene synthase inhibitors include, for example, squalestatin1; squalen epoxydase inhibitors include, for example, NB-598((E)-N-ethyl-N-(6,6-dimethyl-2-heptyn-4-ynyl)-3-[(3,3′-bithiophen-5-yl)methoxy]benzenemethanamine hydrochloride). One or over two agents chosenfrom those are used in the present invention.

Also, fibrate-type cholesterol lowering agents using in the presentinvention is at least one sort chosen from the group consisting ofclofibrate, bezafibrate, cinfibrate, fenofibrate, gemfibrogyl andAHL-157.

The medicine in the present invention is administered in oral dosage ornon-oral dosage form. And, combined usage of a compound represented bythe general formula (I) or pharmaceutical acceptable salts andcholesterol biosynthesis inhibitors and/or fibrate-type cholesterollowering agents can be carried out in various forms. For example, acompound represented by the general formula (I) or pharmaceuticalacceptable salts and cholesterol biosynthesis inhibitors and/orfibrate-type cholesterol lowering agents are mixtured at thepredetermined ratio, furthermore, it is able to form a combination agentwhich blended additives and excipients according to the request (apowder agent, a tablet, a granule agent, a capsule agent, a liquidagent, a suspended agent, a suppository, an ointment agent, aninhalation agent and others). Additives and excipients are lubricants,binders, collapses, fillers, buffers, emulsifiers, preservatives,anti-oxidants, coloring agents, coating agents, suspending agents andothers.

Also, it is able to form a kit by single packaging a containercontaining a compound represented by the general formula (I) orpharmaceutical acceptable salts and a container containing cholesterolbiosynthesis inhibitors and/or fibrate-type cholesterol lowering agents.Also, it is able to administer a compound represented by the generalformula (I) or pharmaceutical acceptable salts and cholesterolbiosynthesis inhibitors and/or fibrate-type cholesterol lowering agentssimultaneously or consecutively.

The daily dose of the medicine in the present invention is determined bythe potency of the compound administered, the weight, age, and conditionof the patient and others. Also, the medicine is administered in asingle dose or 2˜5 divided doses depending oral dosage or non-oraldosage forms. A compound represented by the general formula (I) orpharmaceutical acceptable salts are administered the amount of 0.1˜100mg/kg (mammalian weight) per day in division. Cholesterol biosynthesisinhibitors are administered the amount of 1 mg˜3 g/kg (mammalian weight)per day in division, and for HMG-CoA reductase inhibitors areadministered the amount of 5˜100 mg/kg (mammalian weight) per day indivision. For fibrate-type cholesterol lowering agents are administeredthe amount of 1˜1000 mg/kg (mammalian weight) per day in division.

EXAMPLE

In the pharmacological experiments of this example, the compound ofcompound No. 56 (called compound 56 as following) and the compound ofcompound No. 37 (called compound 37 as following) in the above Tablewere used as a compound represented by the general formula (I) orpharmaceutical acceptable salts.

Pharmacological Experiment 1

The pharmacological experiment of serum cholesterol lowering action bythe combination of compound 56 and atorvastatin or fenofibrate incholesterol-fed rat.

Male Splague-Dawley rats weighing 300˜500 g (Nihon SLC Co. Ltd.) werefed MF-2 chow (Nihon Crea Co. Ltd.) until study onset. At the studyonset, the chow was changed to MF-2 chow containing 1% cholesterol and0.5% cholic acid. Compound 56 at 0.3 mg/kg, atorvastatin at 1 mg/kg orfenofibrate at 10 mg/kg dissolved in polyethylene glycol 400 weresimultaneously administered once a day for 7 days. Twenty hours afterthe last administration, blood was collected from the abdominal aortaunder ether anaesthesia, and serum was separated. The cholesterol valuewas measured using Cholesterol E Test Wako (Wako Pure Chemical Co.Ltd.). Furthermore, the effect of combined dosage of compound 56 at 0.3mg/kg and atorvastatin at 1 mg/kg or fenofibrate at 10 mg/kg wereexamined similarly. The results were shown in Table 13. The experimentalNo. of 1˜3, 4 and 5 indicates the case of compound 56 alone,atrovastatin alone and fenofibrate alone, respectively. The experimental5 and 6 indicates the combined dosage examples in the present invention.Each reduction percent is shown as the value to control. TABLE 13Reduction % Experi- Number of serum mental Dose per cholesterol No.Group (mg/kg/day) group value 1 Compound 56 0.03 6 1.9 2 Compound 56 0.36 6.9 3 Compound 56 1 6 33.5 4 Atorvastatin 1 6 6.2 5 Fenofibrate 10 610.7 6 Compound 56 0.3 6 20.2 Atorvastatin 1 7 Compound 56 0.3 6 41.3Fenofibrate 10

From Table 13, in the case of combined dosage compound 56 at 0.3mg/kg/day and atrovastatin 1 mg/kg/day (Experimental No. 6), andcompound 56 at 0.3 mg/kg/day and fenofibrate at 10 mg/kg/day(Experimental No. 7), each reduction % of serum cholesterol value wasover the sum of reduction % when each agent was administered alone(Experimental No. 2, 4 and 5), indicating synergistic effect.

Pharmacological Experiment 2

Except of the use of compound 37 instead of compound 56, quietly sameexperiment to pharmacological experiment 1 was carried out. The resultswere shown in Table 14. Each reduction % is shown as the value tocontrol. TABLE 14 Reduction % Experi- Number of serum mental Dose percholesterol No. Group (mg/kg/day) group value 11 Compound 37 0.03 6 5.612 Compound 37 0.3 6 18.0 13 Compound 37 1 6 31.0 14 Atorvastatin 1 66.2 15 Fenofibrate 10 6 10.7 16 Compound 37 0.3 6 31.5 Atorvastatin 1 17Compound 37 0.3 6 39.5 Fenofibrate 10

From Table 14, in the case of combined dosage compound 37 at 0.3mg/kg/day and atrovastatin 1 mg/kg/day (Experimental No. 16), andcompound 37 at 0.3 mg/kg/day and fenofibrate at 10 mg/kg/day(Experimental No. 17), the reduction % of serum cholesterol values wereover the sum of reduction % when each agent was administered alone(Experimental No. 12, 14 and 15), indicating synergistic effect.

INDUSTRIAL APPLICABILITY

The medicine consist of the combination of a compound represented by thefollowing general formula (I) or pharmaceutical acceptable salts andcholesterol biosynthesis inhibitors and/or fibrate-type cholesterollowering agents show the synergistic effect and an excellent serumcholesterol lowering effect or preventive or therapeutic effect foratherosclerosis. Therefore, it is useful for serum cholesterolollowering or preventive or therapy for atherosclerosis.

1. Serum cholesterol lowering agent or preventive or therapeutic agentfor atherosclerosis consist of the combination of a compound representedby the following general formula (I) or pharmaceutical acceptable saltsand cholesterol biosynthesis inhibitors and/or fibrate-type cholesterollowering agents,

wherein A₁, A₃ and A₄ are hydrogen atom, halogen atom, alkyl grouphaving one to five carbon atoms, alkoxy group having one to five carbonatoms, —COOR₁, a group represented by following formula

wherein R₁ is hydrogen atom or alkyl group having one to five carbonatoms, or a group represented by following formula (a)

wherein R₂ is —CH₂OH group, —CH₂OC(O)—R₁ group or —CO₂—R₁ group; R₃ is—OH group or —OC(O)—R₁ group; R₄ is —(CH₂)_(k)R₅(CH₂)_(l)—, wherein kand 1 are an integer of 0 or more than 1; k+1 is 10 or fewer integer,and R₄ group binds to tetrahydropyran ring by C—C bond, further, R₅means single bond (—), —CH═CH—, —OCH₂—, carbonyl group or —CH(OH)—, andmore than one of A₁, A₃ and A₄ in formula (I) must be the group inabove-mentioned formula (a), A₂ is alkyl chain having one to five carbonatoms, alkoxy chain having one to five carbon atoms, alkenyl chainhaving one to five carbon atoms, hydroxyl alkyl chain having one to fivecarbon atoms or carbonyl alkyl chain having one to five carbon atoms. n,p, q or r are 0, 1 or
 2. 2. Serum cholesterol lowering agent orpreventive or therapeutic agent for atherosclerosis describe in claim 1consist of the mixture of a compound represented by the above generalformula (I) or pharmaceutical acceptable salts and cholesterolbiosynthesis inhibitors and/or fibrate-type cholesterol lowering agents.3. Serum cholesterol lowering agent or preventive or therapeutic agentfor atherosclerosis formed a kit by single packaging a containercontaining a compound represented by the above general formula (I) orpharmaceutical acceptable salts and a container containing cholesterolbiosynthesis inhibitor and/or fibrate-type cholesterol lowering agents.4. Serum cholesterol lowering agent or preventive or therapeutic agentfor atherosclerosis according to claim 1 consist of a compound which theabove-mentioned general formula (I) is the following formula.


5. Serum cholesterol lowering agent or preventive or therapeutic agentfor atherosclerosis according to claim 1 consist of a compound which theabove-mentioned general formula (I) is the following formula.


6. Serum cholesterol lowering agent or preventive or therapeutic agentfor atherosclerosis according to claim 1 characterized by the use of thecholesterol biosynthesis inhibitors which is at least one sort chosenfrom the group consisting of HMG-COA reductase inhibitors, squalenesynthase inhibitors and squalene epoxydase inhibitors.
 7. Serumcholesterol lowering agent or preventive or therapeutic agent foratherosclerosis according to claim 1 characterized by the use offibrate-type cholesterol lowering agents which is at least one sortchosen from the group consisting of clofibrate, bezafibrate, cinfibrate,fenofibrate, gemfibrogyl and AHL-157.
 8. A dosage method of serumcholesterol lowering agent or preventive or therapeutic agent foratherosclerosis characterized by the administration of a compoundrepresented by the above-mentioned formula (I) or pharmaceuticalacceptable salts and cholesterol biosynthesis inhibitors and/orfibrate-type cholesterol lowering agents simultaneously orconsecutively.
 9. Serum cholesterol lowering agent or preventive ortherapeutic agent for atherosclerosis according to claim 2 consist of acompound which the above-mentioned general formula (I) is the followingformula.


10. Serum cholesterol lowering agent or preventive or therapeutic agentfor atherosclerosis according to claim 3 consist of a compound which theabove-mentioned general formula (I) is the following formula.


11. Serum cholesterol lowering agent or preventive or therapeutic agentfor atherosclerosis according to claim 2 consist of a compound which theabove-mentioned general formula (I) is the following formula.


12. Serum cholesterol lowering agent or preventive or therapeutic agentfor atherosclerosis according to claim 3 consist of a compound which theabove-mentioned general formula (I) is the following formula.


13. Serum cholesterol lowering agent or preventive or therapeutic agentfor atherosclerosis according to claim 2 characterized by the use of thecholesterol biosynthesis inhibitors which is at least one sort chosenfrom the group consisting of HMG-COA reductase inhibitors, squalenesynthase inhibitors and squalene epoxydase inhibitors.
 14. Serumcholesterol lowering agent or preventive or therapeutic agent foratherosclerosis according to claim 3 characterized by the use of thecholesterol biosynthesis inhibitors which is at least one sort chosenfrom the group consisting of HMG-CoA reductase inhibitors, squalenesynthase inhibitors and squalene epoxydase inhibitors.
 15. Serumcholesterol lowering agent or preventive or therapeutic agent foratherosclerosis according to claim 4 characterized by the use of thecholesterol biosynthesis inhibitors which is at least one sort chosenfrom the group consisting of HMG-CoA reductase inhibitors, squalenesynthase inhibitors and squalene epoxydase inhibitors.
 16. Serumcholesterol lowering agent or preventive or therapeutic agent foratherosclerosis according to claim 9 characterized by the use of thecholesterol biosynthesis inhibitors which is at least one sort chosenfrom the group consisting of HMG-CoA reductase inhibitors, squalenesynthase inhibitors and squalene epoxydase inhibitors.
 17. Serumcholesterol lowering agent or preventive or therapeutic agent foratherosclerosis according to claim 10 characterized by the use of thecholesterol biosynthesis inhibitors which is at least one sort chosenfrom the group consisting of HMG-CoA reductase inhibitors, squalenesynthase inhibitors and squalene epoxydase inhibitors.
 18. Serumcholesterol lowering agent or preventive or therapeutic agent foratherosclerosis according to claim 5 characterized by the use of thecholesterol biosynthesis inhibitors which is at least one sort chosenfrom the group consisting of HMG-CoA reductase inhibitors, squalenesynthase inhibitors and squalene epoxydase inhibitors.
 19. Serumcholesterol lowering agent or preventive or therapeutic agent foratherosclerosis according to claim 11 characterized by the use of thecholesterol biosynthesis inhibitors which is at least one sort chosenfrom the group consisting of HMG-COA reductase inhibitors, squalenesynthase inhibitors and squalene epoxydase inhibitors.
 20. Serumcholesterol lowering agent or preventive or therapeutic agent foratherosclerosis according to claim 12 characterized by the use of thecholesterol biosynthesis inhibitors which is at least one sort chosenfrom the group consisting of HMG-COA reductase inhibitors, squalenesynthase inhibitors and squalene epoxydase inhibitors.
 21. Serumcholesterol lowering agent or preventive or therapeutic agent foratherosclerosis according to claim 2 characterized by the use offibrate-type cholesterol lowering agents which is at least one sortchosen from the group consisting of clofibrate, bezafibrate, cinfibrate,fenofibrate, gemfibrogyl and AHL-157.
 22. Serum cholesterol loweringagent or preventive or therapeutic agent for atherosclerosis accordingto claim 3 characterized by the use of fibrate-type cholesterol loweringagents which is at least one sort chosen from the group consisting ofclofibrate, bezafibrate, cinfibrate, fenofibrate, gemfibrogyl andAHL-157.
 23. Serum cholesterol lowering agent or preventive ortherapeutic agent for atherosclerosis according to claim 4 characterizedby the use of fibrate-type cholesterol lowering agents which is at leastone sort chosen from the group consisting of clofibrate, bezafibrate,cinfibrate, fenofibrate, gemfibrogyl and AHL-157.
 24. Serum cholesterollowering agent or preventive or therapeutic agent for atherosclerosisaccording to claim 9 characterized by the use of fibrate-typecholesterol lowering agents which is at least one sort chosen from thegroup consisting of clofibrate, bezafibrate, cinfibrate, fenofibrate,gemfibrogyl and AHL-157.
 25. Serum cholesterol lowering agent orpreventive or therapeutic agent for atherosclerosis according to claim10 characterized by the use of fibrate-type cholesterol lowering agentswhich is at least one sort chosen from the group consisting ofclofibrate, bezafibrate, cinfibrate, fenofibrate, gemfibrogyl andAHL-157.
 26. Serum cholesterol lowering agent or preventive ortherapeutic agent for atherosclerosis according to claim 5 characterizedby the use of fibrate-type cholesterol lowering agents which is at leastone sort chosen from the group consisting of clofibrate, bezafibrate,cinfibrate, fenofibrate, gemfibrogyl and AHL-157.
 27. Serum cholesterollowering agent or preventive or therapeutic agent for atherosclerosisaccording to claim 11 characterized by the use of fibrate-typecholesterol lowering agents which is at least one sort chosen from thegroup consisting of clofibrate, bezafibrate, cinfibrate, fenofibrate,gemfibrogyl and AHL-157.
 28. Serum cholesterol lowering agent orpreventive or therapeutic agent for atherosclerosis according to claim12 characterized by the use of fibrate-type cholesterol lowering agentswhich is at least one sort chosen from the group consisting ofclofibrate, bezafibrate, cinfibrate, fenofibrate, gemfibrogyl andAHL-157.